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(American Journal of Pathology. 2006;169:258-267.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060036

Disabled-2 Heterozygous Mice Are Predisposed to Endometrial and Ovarian Tumorigenesis and Exhibit Sex-Biased Embryonic Lethality in a p53-Null Background

Dong-Hua Yang*, Zia Fazili{dagger}, Elizabeth R. Smith*, Kathy Qi Cai*, Andres Klein-Szanto*, Cynthia Cohen{ddagger}, Ira R. Horowitz§ and Xiang-Xi Xu*

From the Ovarian Cancer and Tumor Cell Biology Programs,* Fox Chase Cancer Center, Philadelphia, Pennsylvania; the Department of Pathology,{ddagger} and the Department of Gynecology and Obstetrics,§ Division of Gynecologic Oncology, Winship Cancer Center,{dagger} Emory University School of Medicine, Atlanta, Georgia

Disabled-2 (Dab2) is a phosphoprotein involved in cellular signal transduction and endocytic trafficking. The expression of Dab2 is frequently lost or suppressed in several epithelial tumors, and studies of its cellular function and growth suppressive activity when re-expressed in cancer cells led to the suggestion that Dab2 is a tumor suppressor. A role for Dab2 in epithelial cell positioning organization was derived from study of knockout mice: homozygous deletion of dab2 results in early embryonic lethality due to the disorganization of the primitive endoderm, the first epithelium in early embryos. We now report that dab2 heterozygous mice develop uterine hyperplasia and ovarian preneoplastic morphological changes at a high frequency. Crossing into a p53–/– background unexpectedly produced few female dab2+/–:p53–/– mice, while the male dab2+/–:p53–/– were born at the expected Mendelian frequency. The tumor-prone phenotype of dab2+/– mice provides additional support for a role of human Dab2 as a tumor suppressor, and the sex-biased embryonic lethality suggests a genetic interaction between p53 and dab2 genes in female mice.




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